In order for T cells to respond to foreign proteins, two signals must be provided by antigen-presenting cells (APCs) to resting T lymphocytes (Jenkins, M. and Schwartz, R. (1987) J. Exp. Med. 165:302–319; Mueller, D. L. et al. (1990) J. Immunol. 144:3701–3709). The first signal, which confers specificity to the immune response, is transduced via the T cell receptor (TCR) following recognition of foreign antigenic peptide presented in the context of the major histocompatibility complex (MHC). The second signal, termed costimulation, induces T cells to proliferate and become functional (Lenschow et al. (1996) Annu. Rev. Immunol. 14:233). Costimulation is neither antigen-specific, nor MHC restricted and is thought to be provided by one or more distinct cell surface molecules expressed by APCs (Jenkins, M. K. et al. (1988) J. Immunol. 140:3324–3330; Linsley, P. S. et al. (1991) J. Exp. Med. 173:721–730; Gimmi, C. D. et al. 1991 Proc. Natl. Acad. Sci. USA 88:6575–6579; Young, J. W. et al. (1992) J. Clin. Invest. 90:229–237; Koulova, L. et al. (1991) J. Exp. Med. 173:759–762; Reiser, H. et al. (1992) Proc. Natl. Acad. Sci. USA 89:271–275; van-Seventer, G. A. et al. (1990) J. Immunol. 144:4579–4586; LaSalle, J. M. et al. (1991) J. Immunol. 147:774–80; Dustin, M. I. et al. (1989) J. Exp. Med. 169:503; Armitage, R. J. et al. (1992) Nature 357:80–82; Liu, Y. et al. (1992) J. Exp. Med. 175:437–445).
The CD80 (B7-1) and CD86 (B7-2) proteins, expressed on APCs, are critical costimulatory molecules (Freeman et al. (1991) J. Exp. Med. 174:625; Freeman et al. (1989) J. Immunol. 143:2714; Azuma et al. (1993) Nature 366:76; Freeman et al. (1993) Science 262:909). B7-2 appears to play a predominant role during primary immune responses, while B7-1, which is upregulated later in the course of an immune response, may be important in prolonging primary T cell responses or costimulating secondary T cell responses (Bluestone (1995) Immunity 2:555).
One receptor to which B7-1 and B7-2 bind, CD28, is constitutively expressed on resting T cells and increases in expression after activation. After signaling through the T cell receptor, ligation of CD28 and transduction of a costimulatory signal induces T cells to proliferate and secrete IL-2 (Linsley, P. S. et al. (1991) J. Exp. Med. 173:721–730; Gimmi, C. D. et al. (1991) Proc. Natl. Acad. Sci. USA 88:6575–6579; June, C. H. et al. (1990) Immunol. Today. 11:211–6; Harding, F. A. et al. (1992) Nature 356:607–609). A second receptor, termed CTLA4 (CD152) is homologous to CD28 but is not expressed on resting T cells and appears following T cell activation (Brunet, J. F. et al. (1987) Nature 328:267–270). CTLA4 appears to be critical in negative regulation of T cell responses (Waterhouse et al. (1995) Science 270:985). Blockade of CTLA4 has been found to remove inhibitory signals, while aggregation of CTLA4 has been found to provide inhibitory signals that downregulate T cell responses (Allison and Krummel (1995) Science 270:932). The B7 molecules have a higher affinity for CTLA4 than for CD28 (Linsley, P. S. et al. (1991) J. Exp. Med. 174:561–569) and B7-1 and B7-2 have been found to bind to distinct regions of the CTLA4 molecule and have different kinetics of binding to CTLA4 (Linsley et al. (1994) Immunity 1:793). A new molecule related to CD28 and CTLA4, ICOS, has been identified and seems to be important in IL-10 production (Hutloff et al. (1999) Nature 397:263; WO 98/38216), as has its ligand, which is a new B7 family member (Aicher A. et al. (2000) J. Immunol. 164:4689–96; Mages H. W. et al. (2000) Eur. J. Immunol. 30:1040-7; Brodie D. et al. (2000) Curr. Biol. 10:333–6; Ling V. et al. (2000) J. Immunol. 164:1653–7; Yoshinaga S. K. et al. (1999) Nature 402:827–32). If T cells are only stimulated through the T cell receptor, without receiving an additional costimulatory signal, they become nonresponsive, anergic, or die, resulting in downmodulation of the immune response.
The importance of the B7:CD28/CTLA4 costimulatory pathway has been demonstrated in vitro and in several in vivo model systems. Blockade of this costimulatory pathway results in the development of antigen specific tolerance in murine and human systems (Harding, F. A. et al. (1992) Nature 356:607–609; Lenschow, D. J. et al. (1992) Science 257:789–792; Turka, L. A. et al. (1992) Proc. Natl. Acad. Sci. USA 89:11102–11105; Gimmi, C. D. et al. (1993) Proc. Natl. Acad. Sci. USA 90:6586–6590; Boussiotis, V. et al. (1993) J. Exp. Med. 178:1753–1763). Conversely, expression of B7 by B7 negative murine tumor cells induces T-cell mediated specific immunity accompanied by tumor rejection and long lasting protection to tumor challenge (Chen, L. et al. (1992) Cell 71:1093–1102; Townsend, S. E. and Allison, J. P. (1993) Science 259:368–370; Baskar, S. et al. (1993) Proc. Natl. Acad. Sci. 90:5687–5690.). Therefore, manipulation of the costimulatory pathways offers great potential to stimulate or suppress immune responses in humans.